CAH5A_HUMAN
ID CAH5A_HUMAN Reviewed; 305 AA.
AC P35218; B2RPF2;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1994, sequence version 1.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=Carbonic anhydrase 5A, mitochondrial {ECO:0000305|PubMed:8356065};
DE EC=4.2.1.1 {ECO:0000269|PubMed:24530203, ECO:0000269|PubMed:8356065};
DE AltName: Full=Carbonate dehydratase VA;
DE AltName: Full=Carbonic anhydrase VA;
DE Short=CA-VA;
DE Flags: Precursor;
GN Name=CA5A {ECO:0000312|HGNC:HGNC:1377}; Synonyms=CA5;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, FUNCTION, CATALYTIC
RP ACTIVITY, SUBCELLULAR LOCATION, AND TRANSIT PEPTIDE.
RC TISSUE=Liver;
RX PubMed=8356065; DOI=10.1073/pnas.90.16.7623;
RA Nagao Y., Platero J.S., Waheed A., Sly W.S.;
RT "Human mitochondrial carbonic anhydrase: cDNA cloning, expression,
RT subcellular localization, and mapping to chromosome 16.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:7623-7627(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Umbilical cord;
RX PubMed=7490083; DOI=10.1006/geno.1995.1177;
RA Nagao Y., Batanian J.R., Clemente M.F., Sly W.S.;
RT "Genomic organization of the human gene (CA5) and pseudogene for
RT mitochondrial carbonic anhydrase V and their localization to chromosomes
RT 16q and 16p.";
RL Genomics 28:477-484(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=16807956; DOI=10.1002/chem.200600159;
RA Temperini C., Scozzafava A., Vullo D., Supuran C.T.;
RT "Carbonic anhydrase activators. Activation of isozymes I, II, IV, VA, VII,
RT and XIV with l- and d-histidine and crystallographic analysis of their
RT adducts with isoform II: engineering proton-transfer processes within the
RT active site of an enzyme.";
RL Chemistry 12:7057-7066(2006).
RN [6]
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=16686544; DOI=10.1021/jm0603320;
RA Temperini C., Scozzafava A., Vullo D., Supuran C.T.;
RT "Carbonic anhydrase activators. Activation of isoforms I, II, IV, VA, VII,
RT and XIV with L- and D-phenylalanine and crystallographic analysis of their
RT adducts with isozyme II: stereospecific recognition within the active site
RT of an enzyme and its consequences for the drug design.";
RL J. Med. Chem. 49:3019-3027(2006).
RN [7]
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=17127057; DOI=10.1016/j.bmcl.2006.11.027;
RA Temperini C., Innocenti A., Scozzafava A., Mastrolorenzo A., Supuran C.T.;
RT "Carbonic anhydrase activators: L-Adrenaline plugs the active site entrance
RT of isozyme II, activating better isoforms I, IV, VA, VII, and XIV.";
RL Bioorg. Med. Chem. Lett. 17:628-635(2007).
RN [8]
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=17314045; DOI=10.1016/j.bmcl.2007.01.113;
RA Temperini C., Innocenti A., Guerri A., Scozzafava A., Rusconi S.,
RA Supuran C.T.;
RT "Phosph(on)ate as a zinc-binding group in metalloenzyme inhibitors: X-ray
RT crystal structure of the antiviral drug foscarnet complexed to human
RT carbonic anhydrase I.";
RL Bioorg. Med. Chem. Lett. 17:2210-2215(2007).
RN [9]
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=19186056; DOI=10.1016/j.bmcl.2009.01.038;
RA Crocetti L., Maresca A., Temperini C., Hall R.A., Scozzafava A.,
RA Muehlschlegel F.A., Supuran C.T.;
RT "A thiabendazole sulfonamide shows potent inhibitory activity against
RT mammalian and nematode alpha-carbonic anhydrases.";
RL Bioorg. Med. Chem. Lett. 19:1371-1375(2009).
RN [10]
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=19206230; DOI=10.1021/ja809683v;
RA Maresca A., Temperini C., Vu H., Pham N.B., Poulsen S.-A., Scozzafava A.,
RA Quinn R.J., Supuran C.T.;
RT "Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new
RT class of suicide inhibitors.";
RL J. Am. Chem. Soc. 131:3057-3062(2009).
RN [11]
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY REGULATION.
RX PubMed=18618712; DOI=10.1002/prot.22144;
RA Di Fiore A., Monti S.M., Hilvo M., Parkkila S., Romano V., Scaloni A.,
RA Pedone C., Scozzafava A., Supuran C.T., De Simone G.;
RT "Crystal structure of human carbonic anhydrase XIII and its complex with
RT the inhibitor acetazolamide.";
RL Proteins 74:164-175(2009).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [13]
RP VARIANT CA5AD PRO-233, CHARACTERIZATION OF VARIANT CA5AD PRO-233, FUNCTION,
RP AND CATALYTIC ACTIVITY.
RX PubMed=24530203; DOI=10.1016/j.ajhg.2014.01.006;
RA van Karnebeek C.D., Sly W.S., Ross C.J., Salvarinova R., Yaplito-Lee J.,
RA Santra S., Shyr C., Horvath G.A., Eydoux P., Lehman A.M., Bernard V.,
RA Newlove T., Ukpeh H., Chakrapani A., Preece M.A., Ball S., Pitt J.,
RA Vallance H.D., Coulter-Mackie M., Nguyen H., Zhang L.H., Bhavsar A.P.,
RA Sinclair G., Waheed A., Wasserman W.W., Stockler-Ipsiroglu S.;
RT "Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A
RT alterations presents with hyperammonemia in early childhood.";
RL Am. J. Hum. Genet. 94:453-461(2014).
CC -!- FUNCTION: Mitochondrial carbonic anhydrase that catalyzes the
CC reversible conversion of carbon dioxide to bicarbonate/HCO3
CC (PubMed:8356065, PubMed:24530203). Mitochondria are impermeable to
CC HCO3, and thus this intramitochondrial carbonic anhydrase is pivotal in
CC providing HCO3 for multiple mitochondrial enzymes that catalyze the
CC formation of essential metabolites of intermediary metabolism in the
CC urea and Krebs cycles (PubMed:24530203). {ECO:0000269|PubMed:24530203,
CC ECO:0000269|PubMed:8356065}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + hydrogencarbonate = CO2 + H2O; Xref=Rhea:RHEA:10748,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:17544; EC=4.2.1.1; Evidence={ECO:0000269|PubMed:16686544,
CC ECO:0000269|PubMed:16807956, ECO:0000269|PubMed:17127057,
CC ECO:0000269|PubMed:17314045, ECO:0000269|PubMed:18618712,
CC ECO:0000269|PubMed:19186056, ECO:0000269|PubMed:19206230,
CC ECO:0000269|PubMed:24530203, ECO:0000269|PubMed:8356065};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10749;
CC Evidence={ECO:0000305|PubMed:24530203};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:10750;
CC Evidence={ECO:0000269|PubMed:24530203};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P23589};
CC -!- ACTIVITY REGULATION: Activated by L- and D-histidine (PubMed:16807956).
CC Activated by L- and D-phenylalanine (PubMed:16686544). Activated by L-
CC adrenaline (PubMed:17127057). Inhibited by coumarins, sulfonamide
CC derivatives such as acetazolamide and Foscarnet (phosphonoformate
CC trisodium salt) (PubMed:17314045, PubMed:19186056, PubMed:19206230,
CC PubMed:18618712). Activated by histamine (PubMed:17127057).
CC {ECO:0000269|PubMed:16686544, ECO:0000269|PubMed:16807956,
CC ECO:0000269|PubMed:17127057, ECO:0000269|PubMed:17314045,
CC ECO:0000269|PubMed:18618712, ECO:0000269|PubMed:19186056,
CC ECO:0000269|PubMed:19206230}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=10.0 mM for CO2 {ECO:0000269|PubMed:18618712};
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:8356065}.
CC -!- DISEASE: Hyperammonemia due to carbonic anhydrase VA deficiency (CA5AD)
CC [MIM:615751]: An autosomal recessive inborn error of metabolism,
CC clinically characterized by infantile hyperammonemic encephalopathy.
CC Metabolic abnormalities include hypoglycemia, hyperlactatemia,
CC metabolic acidosis and respiratory alkalosis.
CC {ECO:0000269|PubMed:24530203}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the alpha-carbonic anhydrase family.
CC {ECO:0000305}.
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DR EMBL; L19297; AAA02890.1; -; mRNA.
DR EMBL; U25134; AAC99806.1; -; Genomic_DNA.
DR EMBL; S80181; AAB47048.1; -; Genomic_DNA.
DR EMBL; S80175; AAB47048.1; JOINED; Genomic_DNA.
DR EMBL; S80176; AAB47048.1; JOINED; Genomic_DNA.
DR EMBL; S80177; AAB47048.1; JOINED; Genomic_DNA.
DR EMBL; S80178; AAB47048.1; JOINED; Genomic_DNA.
DR EMBL; S80240; AAB47048.1; JOINED; Genomic_DNA.
DR EMBL; S80180; AAB47048.1; JOINED; Genomic_DNA.
DR EMBL; CH471114; EAW95372.1; -; Genomic_DNA.
DR EMBL; BC137405; AAI37406.1; -; mRNA.
DR EMBL; BC137411; AAI37412.1; -; mRNA.
DR CCDS; CCDS10965.1; -.
DR PIR; A47745; CRHU5.
DR RefSeq; NP_001730.1; NM_001739.1.
DR AlphaFoldDB; P35218; -.
DR SMR; P35218; -.
DR BioGRID; 107218; 50.
DR IntAct; P35218; 2.
DR STRING; 9606.ENSP00000309649; -.
DR BindingDB; P35218; -.
DR ChEMBL; CHEMBL4789; -.
DR DrugBank; DB03385; 4-Methylimidazole.
DR DrugBank; DB00562; Benzthiazide.
DR DrugBank; DB01194; Brinzolamide.
DR DrugBank; DB00606; Cyclothiazide.
DR DrugBank; DB08846; Ellagic acid.
DR DrugBank; DB00909; Zonisamide.
DR DrugCentral; P35218; -.
DR iPTMnet; P35218; -.
DR PhosphoSitePlus; P35218; -.
DR BioMuta; CA5A; -.
DR DMDM; 461680; -.
DR MassIVE; P35218; -.
DR MaxQB; P35218; -.
DR PaxDb; P35218; -.
DR PeptideAtlas; P35218; -.
DR PRIDE; P35218; -.
DR ProteomicsDB; 54984; -.
DR Antibodypedia; 55888; 148 antibodies from 24 providers.
DR DNASU; 763; -.
DR Ensembl; ENST00000649794.3; ENSP00000498065.2; ENSG00000174990.8.
DR GeneID; 763; -.
DR KEGG; hsa:763; -.
DR MANE-Select; ENST00000649794.3; ENSP00000498065.2; NM_001739.2; NP_001730.1.
DR UCSC; uc002fkn.2; human.
DR CTD; 763; -.
DR DisGeNET; 763; -.
DR GeneCards; CA5A; -.
DR GeneReviews; CA5A; -.
DR HGNC; HGNC:1377; CA5A.
DR HPA; ENSG00000174990; Tissue enriched (liver).
DR MalaCards; CA5A; -.
DR MIM; 114761; gene.
DR MIM; 615751; phenotype.
DR neXtProt; NX_P35218; -.
DR OpenTargets; ENSG00000174990; -.
DR Orphanet; 401948; Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.
DR PharmGKB; PA25992; -.
DR VEuPathDB; HostDB:ENSG00000174990; -.
DR eggNOG; KOG0382; Eukaryota.
DR GeneTree; ENSGT00940000162066; -.
DR HOGENOM; CLU_039326_2_1_1; -.
DR InParanoid; P35218; -.
DR OMA; NAWKTSA; -.
DR OrthoDB; 1377476at2759; -.
DR PhylomeDB; P35218; -.
DR TreeFam; TF316425; -.
DR BRENDA; 4.2.1.1; 2681.
DR PathwayCommons; P35218; -.
DR Reactome; R-HSA-1475029; Reversible hydration of carbon dioxide.
DR SABIO-RK; P35218; -.
DR SignaLink; P35218; -.
DR BioGRID-ORCS; 763; 101 hits in 1039 CRISPR screens.
DR ChiTaRS; CA5A; human.
DR GenomeRNAi; 763; -.
DR Pharos; P35218; Tclin.
DR PRO; PR:P35218; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; P35218; protein.
DR Bgee; ENSG00000174990; Expressed in right lobe of liver and 67 other tissues.
DR ExpressionAtlas; P35218; baseline and differential.
DR Genevisible; P35218; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0004089; F:carbonate dehydratase activity; IDA:UniProtKB.
DR GO; GO:0016836; F:hydro-lyase activity; IBA:GO_Central.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006730; P:one-carbon metabolic process; IBA:GO_Central.
DR Gene3D; 3.10.200.10; -; 1.
DR InterPro; IPR001148; CA_dom.
DR InterPro; IPR036398; CA_dom_sf.
DR InterPro; IPR023561; Carbonic_anhydrase_a-class.
DR InterPro; IPR018338; Carbonic_anhydrase_a-class_CS.
DR PANTHER; PTHR18952; PTHR18952; 1.
DR Pfam; PF00194; Carb_anhydrase; 1.
DR SMART; SM01057; Carb_anhydrase; 1.
DR SUPFAM; SSF51069; SSF51069; 1.
DR PROSITE; PS00162; ALPHA_CA_1; 1.
DR PROSITE; PS51144; ALPHA_CA_2; 1.
PE 1: Evidence at protein level;
KW Direct protein sequencing; Disease variant; Lyase; Metal-binding;
KW Mitochondrion; Reference proteome; Transit peptide; Zinc.
FT TRANSIT 1..38
FT /note="Mitochondrion"
FT /evidence="ECO:0000269|PubMed:8356065"
FT CHAIN 39..305
FT /note="Carbonic anhydrase 5A, mitochondrial"
FT /id="PRO_0000004234"
FT DOMAIN 39..296
FT /note="Alpha-carbonic anhydrase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01134"
FT BINDING 130
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P23589"
FT BINDING 132
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P23589"
FT BINDING 155
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P23589"
FT VARIANT 233
FT /note="S -> P (in CA5AD; decreased carbonate dehydratase
FT activity; decreased protein thermal stability;
FT dbSNP:rs587777316)"
FT /evidence="ECO:0000269|PubMed:24530203"
FT /id="VAR_071188"
SQ SEQUENCE 305 AA; 34750 MW; C4E998D269AB1FE5 CRC64;
MLGRNTWKTS AFSFLVEQMW APLWSRSMRP GRWCSQRSCA WQTSNNTLHP LWTVPVSVPG
GTRQSPINIQ WRDSVYDPQL KPLRVSYEAA SCLYIWNTGY LFQVEFDDAT EASGISGGPL
ENHYRLKQFH FHWGAVNEGG SEHTVDGHAY PAELHLVHWN SVKYQNYKEA VVGENGLAVI
GVFLKLGAHH QTLQRLVDIL PEIKHKDARA AMRPFDPSTL LPTCWDYWTY AGSLTTPPLT
ESVTWIIQKE PVEVAPSQLS AFRTLLFSAL GEEEKMMVNN YRPLQPLMNR KVWASFQATN
EGTRS
